Abstract 4475: Targeting c-MET and MAPK pathway in metastatic castration-resistant prostate cancer
Authors: Sergio Ruiz, María Dolores Fenor de la Maza, Juan Francisco Rodríguez Moreno, Elena Sevillano, Paloma Navarro, Sandra Amarilla, Teresa García Donas, Eduardo Caleiras, Juan Carlos Torrego, Jesus García Donas
Journal: Cancer Research (2019)

Abstract Identification of “agnostic” genetic drivers in cancer is foreseen as a major step forward in precision medicine. Thus, treatment selection could be based on the molecular background of the disease rather than on tumor histology in the near future. However clinical validation of most alterations is lacking and only preclinical models are available. We describe a prostate cancer patient refractory to standard therapies that was found to harbor both a c-Met activating mutation and a BRAF fusion that greatly responded to the MEK inhibitor (MEKi) trametinib. EXPERIMENTAL PROCEDURES The Next Generation Sequencing (NGS) platforms (Oncomine Assay and Archer Variant Plex) were used to characterize molecularly FFPE tissue from the primary tumor of a 73 years old man with metastatic castration-resistant prostate cancer (mCRPC) refractory to Docetaxel, Enzalutamide and Radium 223. Immunostaining was performed to evaluate the status of protumoral pathways activated by the identified genomic alterations. RESULTS Oncomine assay detected a pathogenic c-MET mutation that affected the splicing of exon 14 and the patient was included in a clinical trial with a c-MET inhibidor. He developed Grade 3 anemia, G3 bone pain which required major opioids, a rise of PSA over 900 ng/ml and progressive disease as best response. An extended screening using Archer platform detected a SND1/BRAF fusion. Immunohistochemistry revealed homogeneous tumor positive staining for c-MET, and a punctured staining on pERK in FFPE regions with perineural tumor invasion suggesting a critical role of the BRAF fusion in the spread of the disease. After a comprehensive review of the literature a similar model was identified, where the SND1/BAF function raised in a cell culture of gastric cancer as mechanism of resistance to MET inihibitors (Lee NV et al PLoS One 2012). In preclinical experiments the MEKi trametinib induced significant cell mortality. After given written consent, the patient was put on trametinib (2mg/day) under compassionate use. We observed a large decrease of PSA levels to 90 ng/ml after two weeks of treatment, an increase of hemoglobin levels and significant clinical benefit, with no need of analgesics. After two months on treatment the patient continues on tumor response by the time of communication of this abstract. CONCLUSIONS According to our knowledge, this is the first published study able to demonstrate that cancer patients harboring c-MET exon 14 splicing mutation and SND1-BRAF fusion genes could benefit from therapies with MEK inhibitors. Further experimental procedures are needed to validate this hypothesis. 1. Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, et al. (2012) A Novel SND1-BRAF Fusion Confers Resistance to c-Met Inhibitor PF-04217903 in GTL16 Cells though MAPK Activation. PLoS ONE 7(6): e39653. doi:10.1371/journal.pone.0039653. Citation Format: Sergio Ruiz, María Dolores Fenor de la Maza, Juan Francisco Rodríguez Moreno, Elena Sevillano, Paloma Navarro, Sandra Amarilla, Teresa García Donas, Eduardo Caleiras, Juan Carlos Torrego, Jesus García Donas. Targeting c-MET and MAPK pathway in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4475.